Deficiencies in reward and punishment processing are theoretical cornerstones of alcohol and substance dependence, addiction, and other psychopathology. However, most research ignores the fact that contemporary cognitive theory emphasizes two processing modes: a reflective mode where processing is under conscious control and predominantly frontally-mediated, and a reflexive mode that is not under conscious control and is predominantly striatally-mediated. In addition, a detailed understanding of the genetic underpinnings of dual processing modes of reward and punishment is critical to improving our theories of addiction and psychopathology and to translational work focused on developing interventions. Dopamine and serotonin genes are hypothesized to affect reflexive and reflective reward and punishment processing and are therefore the focus of this proposal. The overall goal of this project is to test specific hypotheses regarding dopaminergic and serotonergic genetic variation on reflexive and reflective reward and punishment processing. We use classification learning tasks for which the optimal mode of processing (reflective or reflexive) can be defined rigorously and for which the research team has over 20 years of experience. The proposed studies will also complement a single nucleotide polymorphism approach with a haplotype strategy, which will determine whether additional variants in these dopaminergic and serotonergic genes also influence reward and punishment processing. We will also account for population stratification by testing and statistically controlling for occult population substructure. Aim 1 examines associations between genetic variation in dopaminergic and serotonergic systems with reward and punishment processing when optimal performance is mediated by the reflexive system or by the reflective system. Aim 2 examines the effects of reflexive system genetic variation on reflective-optimal task performance, and reflective system genetic variation on reflexive-optimal task performance. Aim 3 examines the influence of stress on reflexive reward and punishment processing. The proposed studies are the first to attempt to characterize the interactive effects of serotonin, dopamine and stress on cognitive processing of rewards and punishment using contemporary cognitive frameworks. This integrative, interdisciplinary research approach will provide the critical foundation needed for future translational work that examines how these processes go awry in clinical disorders. PUBLIC HEALTH RELEVANCE: Deficiencies in reward and punishment processing are theoretical cornerstones of alcohol and substance dependence, addiction, and other psychopathology, yet little is known about these are affected by task goals, genetic variation or stress. The overall goal of the proposed research is to provide a detailed understanding of the genetic underpinnings of dual processing modes of reward and punishment which is critical to improving our theories of addiction and psychopathology and to translational work focused on developing interventions.